1. Field of the Invention
The present invention relates to stabilizing a drug in a packaged product. More specifically, the present invention relates to a packaging system for the prevention of degradation in pharmaceutical products, particularly controlled release drug delivery devices such as transdermal systems.
2. Description of Related Art
The use of transdermal drug delivery systems or “patches” as a means to topically administer a drug is well known. Such systems dissolve or disperse the drug into a carrier composition, such as a polymeric and/or pressure-sensitive adhesive composition, from which the drug is delivered. These transdermal drug delivery systems typically are affixed adhesively to the skin or mucosa of a user, and the drug diffuses at a controlled rate from a polymer reservoir or layer into the skin or mucosa and absorbed into the blood. Such transdermal systems are described, for example, in U.S. Pat. Nos. 4,814,168, 4,994,267, 5,474,783, 5.656,286, 5,958,446 and 6,024,976, all of which are expressly incorporated by reference in their entireties.
The typical packaging system for a transdermal system involves enclosing it within a packaging material that is sealed to form a container, such as a sealed pouch, in which the system may remain for long periods of time before its removal and use. Several factors must be considered to ensure the storage stability of a packaged transdermal system.
Conventional transdermal systems that incorporate solid or crystalline forms of drugs require that such drugs be dissolved in the polymeric and/or pressure-sensitive adhesive composition in order to deliver a therapeutically effective amount. The ability of a transdermal system to deliver a therapeutically effective amount for the intended duration of use therefore requires that the active agent remain in non-crystalline or dissolved form in the carrier composition prior to use.
The ability of a transdermal system to deliver a therapeutically effective amount for the intended duration of its use further requires that the drug remain stable in its active form (i.e., not degrade, convert, decompose or the like). The therapeutic activity of many drugs is associated with their absolute molecular configuration. Many drugs exist as different structural forms that have the ability to rotate the plane of plane-polarized light (are “chiral”) . In describing such drugs, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and ‘or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. There is no correlation between nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. Thus, D-lactic acid is the same as (−) lactic acid, and L-lactic acid is (+). For a given chemical structure, these chiral compounds exist as a pair of enantiomers (called stereoisomers) which are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Preventing drug degradation can be critical since 50 of the top 100 drugs worldwide exhibit chirality. See, for example, S. C. Stinson, Chemical & Engineering News, American Chemical Society, Washington, D.C., Vol. 76 (Sep. 21, 1998) pg. 83; and “Chiral Drugs,” S. C. Stinson, Chemical & Engineering News, American Chemical Society, Washington, D.C., (Oct. 9, 1995). A case in point is provided by the L-form of the beta-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer. Moreover, certain isomers may actually be deleterious rather than simply inactive or inert. For example, it is suggested that the D-enantiomer of thalidomide is a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer is believed to be a potent teratogen.
Accordingly, any packaging material used to enclose a transdermal system must not absorb, react with, or otherwise adversely affect the drug or other excipients or components used in the transdermal system. For example, U.S. Pat. No. 5,008,110 discloses that certain polyolefin materials used for transdermal devices tend to absorb lipophilic solvents and/or enhancers, which can significantly decrease the drug's solubility in the carrier composition, as well as cause physical failure of the packaging material. U.S. Pat. No. 4,943,435 discloses that nicotine will adversely affect many common transdermal system component materials such as adhesives, membranes, backings and release liners. It has been additionally discovered that methylphenidate, a chiral drug that exists as four enantiomers of which only one is currently known to be significantly pharmacodynamically active, is unstable in the presence of certain types of packaging materials used for transdermal systems.
It is further known that common environmental factors such as the presence of water (in liquid or vapor form), air and light can adversely affect the stability of some drugs. See, for example, U.S. Pat. No. 5,077,104. Such environmental factors can further affect the solubility of the drug in the carrier composition, which in turn can also significantly impact the shelf-life of the transdermal system. For example, the presence of moisture tends to promote crystal growth or formation in many drugs during storage of a transdermal system. Since only solubilized drug is available for delivery out of a transdermal system, any packaging material used to enclose a transdermal system must provide for the control against such environmental factors.
In the manufacture of a packaged transdermal system, the interior of the sealed package may, and often does, contain trapped moisture. The origin of such moisture can include incidental amounts in the transdermal system components or environmental exposure present when the transdermal system was first packaged. To prevent or control the amount of moisture within such a sealed package, various methods have been employed. These methods include drying of raw materials, further drying of the transdermal system or storing in a desiccating atmosphere prior to packaging, vacuum packaging or packaging in a dry room.
However, the ability to prevent or eliminate moisture within the sealed package, especially over long periods of storage, is further dependent on the moisture permeability of the packaging materials. As a result, packaging materials produced of multiple layers, many incorporating metal foils, are typically required to provide an environmental barrier. Such packaging requirements often result in higher costs for materials and production, and require controlled production to achieve a uniform and desired level of moisture impermeability. Such packages may be difficult to open without the aid of mechanical means such as scissors, and, even the best, may still be moisture permeable to some extent.
Although careful control of the manufacturing conditions and packaging materials can reduce the presence of moisture within a sealed pouch containing a transdermal system, the further use of a desiccant is still often required.
The use of a desiccant in packaging products is generally known in the packaging industry. For example, U.S. Pat. No. 5,322,161 discloses a package for packaging moisture sensitive materials. In the '161 patent, the desiccant is present in a desiccant pouch. The desiccant can be molecular sieves and silica gels. The package of the '161 patent also includes heat-sealing layers for sealing the package.
Desiccant materials have also been used in conjunction with pharmaceutical products. For example, U.S. Pat. No. 5,698,217 discloses a method for inhibiting precipitation of a drug in a transdermal system that forms a solid hydrate in the presence of water vapor. The '217 patent achieves this by placing a desiccant material sealed within the same product package containing transdermal system. The desiccant material is further enclosed within its own package. Accordingly, a desiccant-containing package is required for each individual transdermal system. Further, both such desiccant packaging and desiccant materials must be carefully selected to ensure suitability and compatibility (i.e., control problem of contamination) with the drug and other components of the transdermal system to which they are in close proximity or contact.
U.S. Pat. No. 6,050,400 discloses a packaging system for moisture sensitive pharmaceutical substances comprising an inner container permeable to moisture enclosed within an outer container less permeable to moisture and containing a desiccant. The '400 patent does not teach the use of a pouch for transdermal systems that is permeable to moisture vapor while at the same time meeting the requirements for child-resistant packaging.
None of the related art teaches a cost efficient packaging system for transdermal drug delivery systems that incorporates within a container use of a desiccant and a moisture permeable pouch to hold the transdermal system which is inert to the drug and other transdermal components, in order to prevent degradation reactions of the drug that can be caused by contamination from certain packaging materials and moisture, while also providing a child-resistant wrapping for the transdermal system. In addition, none of the related art teaches the importance of controlling packaging materials and moisture to prevent degradation reactions of chiral drugs or pharmaceutically active enantiomer(s) thereof in transdermal systems.
The present invention is directed to stabilizing a drug, particularly a chiral drug or the pharmaceutically active enantiomer(s) thereof, in a carrier composition of a transdermal system prior to the systems use by providing a product packaging system to prevent or control degradation reactions that can result from contamination by certain packaging materials and moisture, while at the same time providing a child-resistant wrapping for the transdermal system.